Substituted cyclohexylamines as central nervous systems agents

ABSTRACT

Substituted cyclohexylamines and derivatives thereof are described, as well as methods for the preparation and pharmaceutical composition of same, which are useful as central nervous system agents and are particularly useful as dopaminergic, serotonergic, antipsychotic, and anxiolytic agents.

This application is a 371 of PCT/US96/13687 filed Aug. 23, 1996 and thisapplication claims the benefit of U.S. Provisional Application No.60/004,193 filed Sep. 22, 1995.

BACKGROUND OF THE INVENTION

The present invention relates to novel substituted cyclohexylamines andderivatives thereof useful as pharmaceutical agents, to methods fortheir production, to pharmaceutical compositions which include thesecompounds and a pharmaceutically acceptable carrier, and topharmaceutical methods of treatment. The novel compounds of the presentinvention are central nervous system agents. More particularly, thenovel compounds of the present invention are both dopaminergic andserotonergic agents.

Compounds which interact with the dopamine D2 (DA D2) receptor have beenshown to be efficacious in the treatment of psychiatric disorders suchas schizophrenia. However, chronic administration of these agents causesvarious movement disorders both clinically and in animal models. It hasbeen shown that administration of compounds that interact with theserotonin-1A (5-HT1A) receptor can block or prevent these extrapyramidalside effects in preclinical models (Neal-Beliveau B. S., et al., J.Pharm. Exp. Ther., 1993;265:207-17). Increases in both dopamine D2 and5-HT1A receptor densities have been observed during postmortem studiesof schizophrenic brains (Hashimoto T., et al., Life Sciences,1991;48:355-363 and references cited therein). Thus, it seems likelyboth DA D2 and 5-HT1A receptors play an important role in the etiologyof schizophrenia. Taken together, these studies suggest that compoundshaving the ability to interact with both dopamine D2 and 5-HT1Areceptors will have increased efficacy in the treatment of schizophreniawhile causing less side effects. The compounds of the present inventionhave potent binding affinity for both the dopamine D2 receptor and the5-HT1A receptor. They also show activity in a behavioral paradigmpredictive of antipsychotic efficacy.

A series of substituted cyclohexanols and cyclohexylamines representedby the formula ##STR1## wherein R is --OR³, wherein R³ is hydrogen,lower alkyl, cycloalkyl, cycloalkylalkyl, aryl lower alkyl, loweralkanoyl, aroyl, or aryl lower alkanoyl; ##STR2## wherein R⁴ and R⁵ areeach independently hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl,aryl, heteroaryl, aryl lower alkyl, heteroaryl lower alkyl, loweralkanoyl, cycloalkanoyl, cycloalkylalkanoyl, aryl lower alkanoyl,heteroaryl lower alkanoyl, aroyl, heteroaroyl, or R⁴ and R⁵ are takentogether with the nitrogen atom to which they are attached to form aring denoted by ##STR3## wherein p is zero or an integer from 1 to 4 andR⁶ is hydrogen, lower alkyl, cycloalkyl, or cycloalkylalkyl ##STR4##wherein X is oxygen or sulfur or ##STR5## wherein R⁶ is as definedabove, or ##STR6## wherein R⁴ and R⁵ are each independently hydrogen,lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aryl lower alkyl, loweralkanoyl, aryl lower alkanoyl, aroyl, or R⁴ and R⁵ are taken togetherwith the oxygen and nitrogen atoms to which they are attached to form aring denoted by ##STR7## wherein q is an integer from 2 to 3 and R⁶ isas defined above;

m is zero or an integer from 1 to 2;

R¹ is hydrogen, aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinylsubstituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower akyl,lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted bylower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2-or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl orhalogen;

n is zero or an integer from 1 to 4;

R² is ##STR8## wherein R⁷ is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-,4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by loweralkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substitutedby lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2-or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl orhalogen;

and the corresponding cis and trans isomers thereof; or apharmaceutically acceptable acid addition salt thereof are disclosed inU.S. Pat. No. 5,047,406 as dopaminergic agents useful as antipsychoticand antihypertensive agents as well as for treatinghyperprolactinaemia-related conditions and central nervous systemdisorders.

A series of 2-(4-phenyl-1-piperazinyl-alkyl)-aminopyrimidine derivativesrepresented by the formula ##STR9## wherein R¹ and R³ may be the same ordifferent and independently represent hydrogen, halogen, an amino group,a hydroxyl group, a straight or branched chain lower alkyl group, astraight or branched chain lower alkoxy group, or a straight or branchedchain hydroxy-lower alkyl group, R² represents hydrogen, halogen, acarboxyl group, a straight or branched chain lower alkyl group, astraight or branched chain lower alkylcarbonyl group, or a straight orbranched chain lower alkyloxycarbonyl group, R⁴ and R⁵ may be the sameor different and independently represent hydrogen, halogen, a straightor branched chain lower alkyl group, or a straight or branched chainlower alkoxy group, and n represents an integer of 2 to 6 or apharmaceutically acceptable acid addition salt thereof are disclosed inU.S. Pat. No. 5,075,308 as therapeutic agents for urinary obstruction.

The compounds of the present invention, unlike the compounds disclosedin U.S. Pat. No. 5,047,406, interact with both the dopamine D2 andserotonergic 1A receptors. Thus, the compounds of the present inventionare useful in the treatment of psychoses such as schizophrenia withoutthe adverse extrapyramidal effects associated with an agent thatinteracts only with the dopamine receptor.

SUMMARY OF THE INVENTION

Accordingly, the present invention is a compound of Formula I ##STR10##wherein R is heteroaryl; R¹ is hydrogen, lower alkyl, cycloalkyl, aryl,or benzyl;

n is an integer from 1 to 2;

R² is ##STR11## wherein R³ is 2-pyrimidinyl, 2-pyrimidinyl substitutedby 1 to 2 substituents selected from the group consisting of

lower alkyl,

lower alkoxy, and

halogen,

2-quinazolinyl,

4-quinazolinyl,

2-, 3-, or 4-pyridinyl,

2- or 3-thienyl,

2-thiazolyl,

2-pyrazinyl,

phenyl, or

phenyl substituted by 1 to 4 substituents selected from the groupconsisting of

lower alkyl,

lower alkoxy,

hydroxy, halogen, and

trifluoromethyl; and the corresponding cis and trans isomers thereof; ora pharmaceutically acceptable acid addition salt thereof.

As dopaminergic and serotonergic agents, the compounds of Formula I areuseful as antipsychotic agents for treating psychoses such asschizophrenia. They are also useful as anxiolytic agents for thetreatment of anxiety.

A still further embodiment of the present invention is a pharmaceuticalcomposition for administering an effective amount of a compound ofFormula I in unit dosage form in the treatment methods mentioned above.

Finally, the present invention is directed to methods for production ofa compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of Formula I, the term "lower alkyl" means a straightor branched hydrocarbon radical having from 1 to 6 carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.

The term "cycloalkyl" means a three- to seven-member saturatedhydrocarbon ring and includes, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term "aryl" means an aromatic radical which is a phenyl group orphenyl group substituted by 1 to 4 substituents selected from loweralkyl, lower alkoxy, hydroxy, halogen, or trifluoromethyl such as, forexample, 4-fluorophenyl, 2-methoxyphenyl, 3-trifluoromethylphenyl,2,3-dichlorophenyl, 2,3-dimethylphenyl, and the like.

The term "heteroaryl" means a heteroaromatic radical which is 2-, 3-, or4-pyridinyl or 2- or 4-pyridinyl substituted by lower alkyl, loweralkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl or 2-,4-, or 5-pyrimidinylsubstituted by 1 to 3 substituents selected from lower alkyl, loweralkoxy, aryl, trifluoromethyl, or halogen, 2- or 4-quinazolinyl,2-pyrazinyl, 2-thiazolyl, 2-benzothiazolyl or 2-benzothiazolylsubstituted by lower alkyl, lower alkoxy or halogen, or2-benzoimidazolyl or 2-benzoimidazolyl substituted by lower alkyl, loweralkoxy, or halogen.

"Lower alkoxy" is O-alkyl of from 1 to 6 carbon atoms as defined abovefor "lower alkyl."

"Halogen" is fluorine, chlorine, bromine, or iodine.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids, such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,phosphorous, and the like, as well as the salts derived from nontoxicorganic acids, such as aliphatic monoand dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Suchsalts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated aresalts of amino acids such as arginate and the like and gluconate,galacturonate (see, for example, Berge S. M., et al., "PharmaceuticalSalts," Journal of Pharmaceutical Science, 1977;66:1-19).

The acid addition salts of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the presentinvention.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

The compounds of the present invention may exist as a mixture of cis andtrans isomers or as the individual cis and trans isomers. The mixture ofisomers as well as the individual isomers are intended to be encompassedwithin the scope of the present invention.

A preferred compound of Formula I is one wherein

R is 2-, 3-, or 4-pyridinyl,

2-,3-, or 4-pyridinyl substituted by lower alkyl,

2- or 4-pyrimidinyl,

2- or 4-pyrimidinyl substituted by 1 to 2 substituents selected fromlower alkyl, lower alkoxy, aryl, trifluoromethyl, or halogen,

4-quinazolinyl,

2-pyrazinyl,

2-thiazolyl,

2-benzothiazolyl,

2-benzoimidazolyl, or

2-benzoimidazolyl substituted by lower alkyl;

R¹ is hydrogen or methyl;

n is an integer of 2;

R² is ##STR12## wherein R³ is 2-pyrimidinyl, 2-, 3-, or 4-pyridinyl,

2- or 3-thienyl,

2-thiazolyl,

2-pyrazinyl,

phenyl, or

phenyl substituted by 1 to 4 substituents selected from the groupconsisting of

lower alkyl,

lower alkoxy,

hydroxy, halogen, and

trifluoromethyl.

Another preferred embodiment is a compound of Formula I wherein

R is 2-, 3-, or 4-pyridinyl,

2-(3-methyl-pyridinyl),

2- or 4-pyrimidinyl,

2-(4-methyl-pyrimidinyl),

2-(5-methyl-pyrimidinyl),

2-(5-methoxy-pyrimidinyl),

2-(5-phenyl-pyrimidinyl),

2-(4-trifluoromethyl-pyrimidinyl),

2-(5-fluoro-pyrimidinyl),

2-(4,6-dimethyl-pyrimidinyl),

4-quinazolinyl,

2-pyrazinyl,

2-thiazolyl,

2-benzothiazolyl, or

2-(1(N)-methyl-H-benzoimidazolyl);

R¹ is hydrogen or methyl;

n is an integer of 2;

R² is ##STR13## wherein R³ is 2-pyrimidinyl, 2-, 3-, or 4-pyridinyl,

2- or 3-thienyl,

2-thiazolyl,

2-pyrazinyl,

phenyl, or

phenyl substituted by 1 to 2 substituents selected from the groupconsisting of

lower alkyl,

lower alkoxy,

hydroxy, halogen, and

trifluoromethyl.

Also preferred is a compound of Formula I wherein

R is 2-quinazolinyl, or

4-quinazolinyl.

Particularly valuable are:

cis-{4-[2-(4-Pyridin-2-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-aminehydrochloride;

trans-{4-[2-(4-Pyridin-2-yl-piperazin-1-yl)ethyl]-cyclohexyl}-pyrimidin-2-yl-amine;

trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine;

trans-(4-{2-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;

trans-(4-{2-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-methyl-pyrimidin-2-yl-amine;

trans-(4-{2-[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;

trans-{4-[2-(4-Pyridin-2-yl-piperazin-1-yl)ethyl]-cyclohexyl}-quinazolin-4-yl-amine;

trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-quinazolin-4-yl-amine;

cis-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-quinazolin-4-yl-amine;

cis-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-aminehydrochloride;

trans-Methyl-{4-[2-(4-phenyl-piperazin-1-yl)ethyl]-cyclohexyl}-pyrimidin-2-yl-amine;

trans-(5-Fluoro-pyrimidin-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;

trans-Pyrimidin-2-yl-(4-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amine;

trans-(4-{2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;

trans-Pyrimidin-2-yl-{4-[2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;

trans-(4-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;

trans-{4-[2-(4-Phenyl-3,6-dihydro-2H-pyridin-1-yl)-ethyl]-cyclohexyl)}-pyrimidin-2-yl-amine;

trans-Pyrimidin-2-yl-{4-[2-(4-thiazol-2-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;

trans-(4-{2-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;

trans-Pyrimidin-2-yl-{4-[2-(2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-yl)-ethyl]-cycohexyl}-amine;

trans-{4-[2-(4-Pyridin-3-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine;

trans-{4-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine;

trans-4-(4-{2-[4-(Pyrimidin-2-ylamino)-cyclohexyl]-ethyl}-piperazin-1-yl)-phenol;

trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyridin-3-yl-amine;

trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyridin-2-yl-amine;

trans-(4-Methyl-pyrimidin-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;

trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-thiazol-2-yl-amine;

trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrazin-2-yl-amine;

trans-Benzothiazol-2-yl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;

cis-(1-Methyl-1H-benzoimidazol-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;

trans-(1-Methyl-1H-benzoimidazol-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;

trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-4-yl-amine;

trans-(3-Methyl-pyridin-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;

trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyridin-4-yl-amine;

trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-trifluoromethyl-pyrimidin-2-yl)-amine;

trans-(5-Methoxy-pyrimidin-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cylohexyl}-amine;

trans-(5-Methyl-pyrimidin-2-yl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;

trans-(5-Phenyl-pyrimidin-2-yl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;and

trans-(4,6-Dimethyl-pyrimidin-2-yl-{4-[2-(4phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;or a pharmaceutically acceptable acid addition salt thereof.

Most particularly valuable is:

trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine;or a pharmaceutically acceptable acid addition salt thereof.

The compounds of Formula I are valuable dopaminergic and serotonergicagents. The tests employed indicate that compounds of Formula I possessdopaminergic and serotonergic activity. Thus, the compounds of Formula Iwere tested for their ability to inhibit spontaneous locomotor activityin mice, a test predictive of antipsychotic activity, according to theassay described by McLean J. R., et al., Pharmacology, Biochemistry andBehavior, 1978;8:97-99; for their ability to bind to the dopamine D2receptor using [³H]-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin ([³ H)N-0437) asthe ligand according to the method disclosed in Van der Weide J., etal., Eur. J. Pharmacol., 1987;134:211-219; and for their ability to bindto the serotonin 5HT1A receptor using [³H]-8-hydroxy-dipropylaminotetralin ([³ H]-8-OH-DPAT) as the ligandaccording to the method disclosed in Peroutka S. J., et al., Brain Res.,1985;344:167-171. The above test methods are incorporated herein byreference. The data in the table show the dopaminergic and serotonergicactivity of representative compounds of Formula I.

    __________________________________________________________________________    Biological Activity of Compounds of Formula I                                                            Inhibition of                                          Inhibition of [.sup.3 H]8-OH-DPAT                                             [.sup.3 H]N-0437 Binding to Rat Inhibition of                                 Binding to h-D2 Hippocampus Locomotor                                       Example  Receptors Membranes Activity in Mice                                 No. Compound (K.sub.i, nM) (K.sub.i, nM) (ED.sub.50, mg/kg, IP)             __________________________________________________________________________     1   cis-{4-[2-(4-Pyridin-2-yl-                                                                  46      8.8     1.2                                           piperazin-1-yl)-ethyl]-                                                       cyclohexyl}-pyrimidin-2-yl-                                                   amine hydrochloride                                                        {4-[2-(4-Pyridin-2-yl- 12   2.2  0.24                                            piperazin-1-yl)-ethyl]-                                                       cyclohexyl}-pyrimidin-2-yl-                                                   amine                                                                      {4-[2-(4-Phenyl- 3.4 3.1 0.3                                                     piperazin-1-yl)-ethyl]-                                                       cyclohexyl}-pyrimidin-2-yl-                                                   amine                                                                      {4-[2-(4-Phenyl-piperazin- 28   1.9                                              1-yl)-ethyl]-cyclohexyl}-                                                     pyrimidin-2-yl-amine                                                          hydrochloride                                                              Pyrimidin-2-yl-(4-{2-[4- 6   13   4.4                                            (3-trifluoromethyl-phenyl}-                                                   piperazin-1-yl]-ethyl]-                                                       cyclohexyl)-amine                                                          (4-{2-[4-(2-Methoxy- 3   0.5 0.5                                                 phenyl)-piperazin-1-yl]-ethyl}-                                               cyclohexyl)-pyrimidin-2-yl-                                                   amine                                                                      (4-{2-[4-(4-Fluoro- 8.3 4.4 0.7                                                  phenyl)-piperazin-1-yl]-ethyl}-                                               cyclohexyl)-pyrimidin-2-yl-                                                   amine                                                                        16 trans-{4-[2-(4-Phenyl-3,6- 4.7 3.9  0.25                                    dihydro-2H-pyridin-1-yl)-                                                     ethyl]-cyclohexyl]-pyrimidin-2-                                               yl-amine                                                                   Pyrimidin-2-yl-{4-[2-(4- 46   10   0.3                                           thiazol-2-yl-piperazin-1-yl)-                                                 ethyl]-cyclohexyl}-amine                                                   {4-[2-(4-Pyridin-3-yl- 25.3  9.5 --                                              piperazin-1-yl)-ethyl]-                                                       cyclohexyl)-pyrimidin-2-yl-                                                   amine                                                                      {4-[2-(4-Phenyl- 1.4 1.2 0.2                                                     piperazin-1-yl)-ethyl]-                                                       cyclohexyl}-pyridin-2-yl-amine                                               26 trans-{4-[2-(4-Phenyl-  2.35 7.9 --                                         piperazin-1-yl)-ethyl]-                                                       cyclohexyl}-thiazol-2-yl-amine                                             {4-[2-(4-Phenyl-  0.93 5.1  0.18                                                 piperazin-1-yl)-ethyl]-                                                       cyclohexyl)-pyrazin-2-yl-amine                                             __________________________________________________________________________

A compound of Formula I ##STR14## wherein R is heteroaryl; R¹ ishydrogen,

lower alkyl,

cycloalkyl,

aryl, or

benzyl;

n is an integer from 1 to 2;

R² is ##STR15## wherein R³ is 2-pyrimidinyl, 2-pyrimidinyl substitutedby 1 to 2 substituents selected from the group consisting of

lower alkyl,

lower alkoxy, and

halogen,

2-quinazolinyl,

4-quinazolinyl,

2-, 3-, or 4-pyridinyl,

2- or 3-thienyl,

2-thiazolyl,

2-pyrazinyl,

phenyl, or

phenyl substituted by 1 to 4 substituents selected from the groupconsisting of

lower alkyl,

lower alkoxy,

hydroxy, halogen, and

trifluoromethyl; and

the corresponding cis and trans isomers thereof; or a pharmaceuticallyacceptable acid addition salt thereof may be prepared by reacting acompound of Formula II ##STR16## wherein R¹, n, and R² are as definedabove with a compound of Formula III

    RX                                                         III

wherein X is Cl or Br and R is as defined above in the presence of abase such as, for example, triethylamine and the like and a solvent suchas, for example, ethanol and the like at about room temperature to thereflux temperature of the solvent to give a compound of Formula I.Preferably, the reaction is carried out in the presence of triethylaminein ethanol at reflux temperature.

A compound of Formula II is prepared from a compound of Formula IV##STR17## wherein n and R² are as defined above and a compound ofFormula V

    R.sup.1 NH.sub.2                                           V

wherein R¹ is as defined above in the presence of a metal hydride suchas, for example, sodium cyanoborohydride and the like in acetic acid anda solvent such as, for example, methanol and the like to give a compoundof Formula II. Preferably, the reaction is carried out in the presenceof sodium cyanoborohydride in acetic acid and methanol.

A compound of Formula IV is prepared from a compound of Formula VI##STR18## wherein m is zero or an integer of 1 and R² is as definedabove in the presence of a metal hydride such as, for example, aluminumhydride and the like in a solvent such as, for example, tetrahydrofuranand the like to give after subsequent treatment of the intermediatecompound with an acid such as, for example, aqueous hydrochloric acidand the like in a solvent such as, for example, acetone and the like toremove the ketal group a compound of Formula IV. Preferably, thereaction is carried out in the presence of aluminum hydride intetrahydrofuran followed by treatment with aqueous hydrochloric acid inacetone to remove the ketal group.

A compound of Formula VI is prepared from a compound of Formula VII##STR19## wherein m is as defined above and a compound of Formula VIII

    R.sup.2 H                                                  VIII

wherein R² is as defined above in the presence of isobutyl chloroformateand the like, and a base such as, for example, triethylamine and thelike and a solvent such as, for example, methylene chloride and the liketo give a compound of Formula VI. Preferably, the reaction is carriedout in the presence of isobutyl chloroformate and triethylamine in themethylene chloride.

A compound of Formula I may exist as a mixture of cis or trans isomersor as the separate cis or trans isomer. Accordingly, as another aspectof the present invention, a mixture of cis and trans isomers of FormulaI may be separated into the individual cis or trans isomer byconventional methodology such as, for example, by fractionalcrystallization, chromatography and the like.

Preferably, the trans isomer of a compound of Formula I ##STR20##wherein R, R¹, n, and R² are as defined above may be prepared byreacting a compound of Formula IX ##STR21## wherein R and n are asdefined above and a compound of Formula VIII

    R.sup.2 H                                                  VIII

wherein R² is as defined above in the presence of a base such as, forexample, potassium carbonate and the like in a solvent such as, forexample, acetonitrile and the like to give the trans isomer of acompound of Formula I. Preferably, the reaction is carried out in thepresence of potassium carbonate in acetonitrile.

A compound of Formula IX is prepared from a compound of Formula X##STR22## wherein R and n are as defined above in the presence ofpolymer supported triphenylphosphine and carbon tetrabromide in asolvent such as, for example, methylene chloride and the like to give acompound of Formula IX. Preferably, the reaction is carried out in thepresence of polymer supported triphenylphosphine and carbon tetrabromidein methylene chloride.

A compound of Formula X is prepared from a compound of Formula XI##STR23## wherein R and m are as defined above in the presence of ametal hydride such as, for example, lithium aluminum hydride and thelike in a solvent such as, for example, tetrahydrofuran and the like togive a compound of Formula X. Preferably, the reaction is carried out inthe presence of lithium aluminum hydride in tetrahydrofuran.

A compound of Formula XI is prepared from a compound of Formula XII##STR24## wherein m is as defined above and a compound of Formula III

    RX                                                         III

wherein R and X are as defined above in the presence of a base such as,for example, triethylamine and the like in a solvent such as, forexample, ethanol and the like at about room temperature to the refluxtemperature of the solvent to give a compound of Formula XI. Preferably,the reaction is carried out in the presence of triethylamine in ethanolat reflux temperature.

Preferably, the trans isomer of a compound of Formula Ia ##STR25##wherein R, R², and n are as defined above may be prepared from acompound of Formula IV ##STR26## wherein n and R² are as defined aboveand a compound of Formula XIII

    R--NH.sub.2                                                XIII

wherein R is as defined above using methodology used to prepare acompound of Formula II from a compound of Formula IV and a compound ofFormula V followed by separation of the isomers using conventionalmethodology such as, for example, chromatography, crystallization, andthe like to afford a compound of Formula Ia.

Preferably, the trans isomer of a compound of Formula Ib ##STR27##wherein R^(a) is 2- or 5-pyrimidinyl substituted by trifluoromethyl orhalogen and R² and n are as defined above may be prepared from acompound of Formula XIV ##STR28## wherein R² and n are as defined aboveand a compound of Formula XV

    R.sup.a X                                                  XV

wherein R^(a) and X are as defined above using the methodology used toprepare a compound of Formula I from a compound of Formula II and acompound of Formula III to afford a compound of Formula Ib.

A compound of Formula XIV is prepared from a compound of Formula XVI##STR29## wherein R² and n are as defined above using the methodologyused to prepare a compound of Formula IV from a compound of Formula VIto afford a compound of Formula XIV.

A compound of Formula XVI is prepared from a compound of Formula XVII##STR30## wherein BOC is tert-butoxycarbonyl and R² and m are as definedabove in the presence of an acid such as, for example, hydrochloric acidand the like to afford a compound of Formula XVI.

A compound of Formula XVII is prepared from a compound of Formula XVIII##STR31## wherein BOC and m are as defined above and a compound ofFormula VIII in the presence of a coupling reagent such as, for example,1-ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride and the likeand a base such as, for example, triethylamine and the like to afford acompound of Formula XVII.

A compound of Formula XVIII is prepared by treating 4-nitrophenyl aceticacid with hydrogen in the presence of a catalyst such as, for example,Raney nickel and the like and a base such as, for example, sodiumhydroxide to afford the 4-aminocyclohexane acetic acid which is treatedin situ with di-tert-butyl dicarbonate and the like in a solvent suchas, for example, tetrahydrofuran and the like to afford a compound ofFormula XVIII.

Preferably, the trans isomer of a compound of Formula Ic ##STR32##wherein R^(b) is 2-pyrimidinyl substituted by lower alkyl, lower alkoxy,aryl, or trifluoromethyl and R² and n are as defined above may beprepared from a compound of Formula XIX ##STR33## wherein R² and n areas defined above and a compound of Formula XX or a compound of FormulaXXI ##STR34## wherein R⁴, R⁵, and R⁶ are each independently the same ordifferent and are lower alkyl, lower alkoxy, aryl, or trifluoromethyl inthe presence of a base such as, for example, sodium methoxide (NaOMe)and the like and a solvent such as, for example, methanol and the liketo afford a compound of Formula Ic.

A compound of Formula XIX is prepared from a compound of Formula XXII##STR35## wherein CBZ is carbobenzyloxy and R² and n are as definedabove by treatment with hydrogen in the presence of a catalyst such as,for example, palladium on carbon and the like to afford a compound ofFormula XIX.

A compound of Formula XXII is prepared from a compound of Formula XIVand S-methyl-N,N¹ -dicarbobenzyloxy isothiourea in the presence of abase such as, for example, triethylamine and the like and a solvent suchas, for example, dimethylformamide and the like to afford a compound ofFormula XXII.

Compounds of Formula III, Formula V, Formula VII, Formula VIII, FormulaXII, Formula XIII, Formula XV, Formula XX, and Formula XXI are eitherknown or capable of being prepared by methods known in the art.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. It will beobvious to those skilled in the art that the following dosage forms maycomprise as the active component, either a compound of Formula I or acorresponding pharmaceutically acceptable salt of a compound of FormulaI.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 1 mg to 1000 mg preferably 10 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as antipsychotic and anxiolytic agents, the compoundsutilized in the pharmaceutical method of this invention are administeredat the initial dosage of about 1 mg to about 50 mg per kilogram daily. Adaily dose range of about 5 mg to about 25 mg per kilogram is preferred.The dosages, however, may be varied depending upon the requirements ofthe patient, the severity of the condition being treated, and thecompound being employed. Determination of the proper dosage for aparticular situation is within the skill of the art. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under the circumstances isreached. For convenience, the total daily dosage may be divided andadministered in portions during the day if desired.

The following nonlimiting examples illustrate the inventors' preferredmethods for preparing the compounds of the invention.

EXAMPLE 1cis-{4-[2-(4-Pyridin-2-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-aminehydrochloride and EXAMPLE 1atrans-{4-[2-(4-Pyridin-2-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine

Step 1: Preparation of2-(1,4-Dioxaspiro[4.5]dec-8yl)-1-[4-(2-pyridinyl)-1-piperazinyl]-ethanone

A solution of (1,4-Dioxaspiro[4.5]dec-8-yl)-acetic acid (U.S. Pat. No.5,124,332) (20.0 g, 99.8 mmol) and triethylamine (21 mL, 149 mmol) in200 mL of methylene chloride (CH₂ Cl₂) was cooled to 0° C. in an icebath and treated with isobutyl chloroformate (13.98 mL, 107.8 mmol).After stirring for 10 minutes 1-(2-pyridinyl)piperazine (17.6 g, 108mmol) is added in 50 mL of methylene chloride. The reaction is removedfrom the ice bath and stirred at room temperature for 24 hours. Thereaction mixture is treated with 200 mL of a saturated sodiumbicarbonate solution. The aqueous layer is separated and extracted withan additional 150 mL of methylene chloride. The combined organicfractions are dried over magnesium sulfate (MgSO₄), and the solvent isremoved under reduced pressure to give an oil which is triturated withdiethyl ether (Et₂ O) to give2-(1,4-dioxaspiro[4.5]dec-8-yl)-1-[4-(2-pyridinyl)-1-piperazinyl]-ethanone(22.7 g) as a white solid.

Step 2: Preparation of4-[2-[4-(2-Pyridinyl)-1-piperazinyl]ethyl]-cyclohexanone

A slurry of lithium aluminum hydride (LiAlH₄) (7.48 g, 197 mmol) in 180mL of tetrahydrofuran (THF) is cooled to 0° C. and treated with aluminumchloride (AlCl₃) (8.76 g, 65.7 mmol) in 180 mL of diethyl ether. Thereaction was stirred for 30 minutes and the2-(1,4dioxaspiro[4.5]dec-8-yl)-1-[4-(2-pyridinyl)-1-piperazinyl]-ethanone(22.7 g, 65.7 mmol) was added in portions over 1 hour. The reaction isallowed to stir for 18 hours and is quenched with 8 mL of water and 18mL of a 50% sodium hydroxide (NaOH) solution. The reaction is stirredfor 1 hour and filtered through a pad of Celite. The filter cake iswashed with 300 mL of diethyl ether. The combined organic extracts areconcentrated to give a white solid which is dissolved in a 230 mL of a1:1 mixture of acetone and 10% aqueous hydrochloric acid (HCl) solution.After stirring at room temperature for 60 hours, the acetone is removedunder reduced pressure, and the pH of the reaction mixture is adjustedto pH 9 with concentrated ammonium hydroxide solution. The aqueousmixture is extracted with two 250 mL portions of chloroform, and thecombined organic fractions are dried with sodium sulfate. The solventsare removed under reduced pressure, and the residue is triturated withdiethyl ether to give 14.3 g4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]-cyclohexanone as a whitesolid.

Step 3: Preparation of mixture of cis andtrans-4-[2-[4-(2-pyridinyl)-1-piperazinyl]-ethyl]-cyclohexanamines

A mixture of 4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]-cyclohexanone(10 g, 36.31 mmol) and ammonium acetate (27.2 g, 360 mmol) are dissolvedin 250 mL methanol (MeOH). The solution is treated with sodiumcyanoborohydride (1.62 g, 25.9 mmol) and stirred at room temperature for18 hours. The solvent is removed under reduced pressure, and the residueis partitioned between chloroform and 2N sodium carbonate (Na₂ CO₃)solution. The organic layer is separated, dried over sodium sulfate, andthe solvents are removed under reduced pressure to give 10.0 g of amixture of cis andtrans-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]-cyclohexanamines as acolorless oil which was used without further purification.

Step 4: Preparation of cis andtrans-{4-[2-(4-pyridin-2-yl-piperazin-1-yl)ethyl]-cyclohexyl}-pyrimidin-2-yl-amine

The mixture of cis andtrans-4-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]-cyclohexanamines (1.95g, 7.05 mmol), 2-chloro-pyrimidine (0.56 g, 7.05 mmol) and triethylamine(0.9 mL) is heated to reflux for 32 hours. The reaction is cooled andthe solvents removed under reduced pressure. The residue is partitionedbetween chloroform and 2N sodium carbonate solution. The organic layeris separated, dried over sodium sulfate, and the solvents are removedunder reduced pressure. The residue is chromatographed over silica gelusing a mixture of chloroform, methanol, and ammonia as the solvents.The separated cis isomer was isolated as the hydrochloride salt; mp 156°C.

The separated trans isomer was recrystallized from ethyl acetate toafford the title compound; mp 140° C.

In a process analogous to Example 1 and Example la using appropriatestarting materials, the corresponding compounds of Formula I (Examples2-11) are prepared as follows:

EXAMPLE 2trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]cyclohexyl}-pyrimidin-2-yl-amine;mp 162° C. EXAMPLE 3trans-(4-{2-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;mp 170° C. EXAMPLE 4trans-(4-{2-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]ethyl}-cyclohexyl)-methyl-pyrimidin-2-yl-amine;mp 95° C. EXAMPLE 5trans-(4-{2-[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;mp 167° C. EXAMPLE 6trans-{4-[2-(4-Pyridin-2-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-quinazolin-4-yl-amine;mp 188° C. EXAMPLE 7trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-quinazolin-4-yl-amine;mp 192° C. EXAMPLE 8cis-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-quinazolin-4-yl-amine;mp 138° C. EXAMPLE 9cis-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-aminehydrochloride; mp 120° C. EXAMPLE 10trans-Methyl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine;mp 134° C. EXAMPLE 11trans-(5-Fluoro-pyrimidin-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;mp 176° C. EXAMPLE 12trans-Pyrimidin-2-yl-(4-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine

Step 1: Preparation of trans-[4-(pyrimidin-2-yl-amino)-cyclohexyl]aceticacid ethyl ester

A solution of trans-(4-Amino-cyclohexyl)-acetic acid ethyl ester(Karapavicius K., Palaima A. I., Knunyants I. L., Izv. Akad. Nauk SSSR,Ser. Khim., 1980;10;2374-9) (3.46 g, 18.7 mmol), 2-chloropyrimidine(2.14 g, 18.7 mmol) and triethylamine (5.21 mL) is refluxed in ethanol(EtOH) (10 mL) for 48 hours. The reaction is cooled, and the solventsare removed under reduced pressure. The residue is partitioned betweenchloroform and 2N aqueous sodium carbonate solution. The organic layeris separated, dried over sodium sulfate, and the solvents are removedunder reduced pressure. The residue is chromatographed over silica gelusing a mixture of chloroform and methanol to givetrans-[4-(pyrimidin-2-ylamino)-cyclohexyl]-acetic acid ethyl ester.

Step 2: Preparation oftrans-2-[4-(pyrimidin-2-ylamino)-cyclohexyl]-ethanol

A suspension of lithium aluminum hydride (0.45 g, 11.85 mmol) is cooledin an ice water bath and treated with a solution oftrans-[4-(pyrimidin-2-ylamino)-cyclohexyl]-acetic acid ethyl ester (2.09g, 7.9 mmol) in THF (15 mL) over 20 minutes. After stirring for 5minutes, the ice bath is removed, and the reaction is stirred for anadditional 40 minutes. The reaction is quenched with water, and sodiumhydroxide is added. The mixture is stirred for 1 hour and is filteredthrough Celite and the filtrate evaporated to givetrans-2-[4-(pyrimidin-2-ylamino)-cyclohexyl]-ethanol which is usedwithout further purification.

Step 3: Preparation oftrans-[4-(2-Bromoethyl)-cyclohexyl]-pyrimidin-2-yl-amine

A mixture of trans-2-[4-(pyrimidin-2-ylamino)-cyclohexyl]-ethanol (1.51g, 6.9 mmol) is dissolved in a solution of methylene chloride (25 mL)containing polymer supported triphenylphosphine (2.87 g, approx 8.6mmol). The mixture is cooled in an ice water bath, and carbontetrabromide (2.3 g, 7.0 mmol) is added. The reaction is stirred for 1hour, and the polymeric material was removed by filtration. The filtrateis concentrated and chromatographed on silica gel using a 2:1 mixture ofchloroform and ethyl acetate (EtOAc) as the solvent to givetrans-[4-(2-Bromoethyl)-cyclohexyl]-pyrimidin-2-yl-amine.

Step 4: Preparation oftrans-Pyrimidin-2-yl-(4-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-amine

A mixture of trans-[4-(2-Bromoethyl)-cyclohexyl]-pyrimidin-2-yl-amine(0.26 g, 0.91 mmol), 1-(3-trifluoromethyl-phenyl)-piperazine (0.21 g,0.91 mmol), and potassium carbonate (0.21 g, 1.5 mmol) was heated in 10mL refluxing acetonitrile for 18 hours. The reaction was diluted withmethylene chloride, filtered, and the solvents were removed underreduced pressure. The residue was partitioned between chloroform andaqueous 2N sodium carbonate solution. The organic layer was dried oversodium sulfate and evaporated. The resulting residue was recrystallizedfrom acetonitrile to give the title compound; mp 167° C.

In a process analogous to Example 12 using appropriate startingmaterials, the corresponding compounds of Formula I (Examples 13-21) areprepared as follows:

EXAMPLE 13trans-(4-{2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;mp 139° C. EXAMPLE 14trans-Pyrimidin-2-yl-{4-[2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;mp 154° C. EXAMPLE 15trans-(4-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;mp 162° C. EXAMPLE 16trans-{4-[2-(4-Phenyl-3,6-dihydro-2H-pyridin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine;mp 146° C. EXAMPLE 17trans-Pyrimidin-2-yl-{4-[2-(4-thiazol-2-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;mp 151° C. EXAMPLE 18trans-(4-{2-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;mp 177° C. EXAMPLE 19trans-Pyrimidin-2-yl-{4-[2-(2,3,5,6-tetrahydro[1,2']-1bipyrazinyl-4-yl)-ethyl]-cyclohexyl}-amine;mp 162° C. EXAMPLE 20trans-{4-[2-(4-Pyridin-3-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine;mp 174-175° C. EXAMPLE 21trans-{4-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine;mp 121-122° C. EXAMPLE 22trans-4-(4-{2-[4-(Pyrimidin-2-ylamino)-cyclohexyl]-ethyl}-piperazin-1-yl)-phenol

A solution oftrans-Pyrimidin-2-yl-{4-[2-(2,3,5,6tetrahydro[1,2']bipyrazinyl-4-yl)-ethyl]-cyclohexyl}-amine(Example 19) in 10 mL of 48% HBr was heated to reflux for 2 hours. Thesolution was evaporated under reduced pressure and then suspended in anaqueous solution which was adjusted to pH 8 by the addition of sodiumhydroxide. The aqueous suspension was extracted with chloroform, and theorganic solution was dried over sodium sulfate and the solvents removedunder reduced pressure. The resulting residue was recrystallized fromacetonitrile to give the title compound as an off-white solid; mp192-194° C.

EXAMPLE 23{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyridin-3-yl-amine

3-Aminopyridine (1.6 g, 16.9 mmol) and the ketone4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexanone (1.09 g, 3.8 mmol)were heated together in toluene (20 mL) under reflux through 4Amolecular sieves (25 g) for 16 hours. The resultant solution of imineintermediate was cooled to room temperature and stirred while a freshlyprepared solution of sodium cyanoborohydride (0.97 g, 15.4 mmol) inmethanol (15 mL) was quickly added. Acetic acid (0.6 mL) was then addeddropwise (Caution: gas evolution). After 2.5 hours at room temperature,the reduction was quenched by the addition of 10% aqueous solution ofNa₂ CO₃ (75 mL). The mixture was vigorously stirred for 40 minutes, thenextracted with diethyl ether (150 mL, 2×60 mL. The extract was driedover MgSO₄ and concentrated under vacuum. The residue (1.49 g) washeated at 90° C. under vacuum (2 mm-Hg) to remove the bulk of the excess3-aminopyridine to leave predominantly a 3:1 mixture of trans and cisisomers of the product. Recrystallization from ethyl acetate (˜10mL)/diethyl ether (˜50 mL) afforded 0.56 g (9:1 trans/cis). A secondrecrystallization from ethyl acetate (˜10 mL) afforded the pure trans(0.42 g); mp 159-160° C.

In a process analogous to Example 23 using appropriate startingmaterials, the corresponding compounds of Formula I (Examples 24-33) areprepared as follows:

EXAMPLE 24trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]cyclohexyl}-pyridin-2-yl-amine;mp 136-138° C. EXAMPLE 25trans-(4-Methyl-pyrimidin-2-yl)-{4-[2-(4-phenyl-perazin-1-yl)-ethyl]-cyclohexyl}-amine;mp 147-148° C. EXAMPLE 26trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-thiazol-2-yl-amine;mp 156-157° C. EXAMPLE 27trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrazin-2-yl-amine;mp 139-140° C. EXAMPLE 28trans-Benzothiazol-2-yl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;mp 187-188° C. EXAMPLE 29cis-(1-Methyl-1H-benzoimidazol-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;mp 124-127° C. EXAMPLE 30trans-(1-Methyl-1H-benzoimidazol-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;mp 162-163° C. EXAMPLE 31trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-4-yl-amine;mp 171° C. EXAMPLE 32trans-(3-Methyl-pyridin-2-yl)-{4-[2-(4-phenylpiperazin-1-yl)-ethyl]-cyclohexyl}-amine;mp 114-115° C. EXAMPLE 33trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyridin-4-yl-amine;mp 185-187° C. EXAMPLE 34trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-trifluoromethyl-pyrimidin-2yl)-amine

Step 1: Preparation oftrans-(4-Tert-butoxycarbonylamino-cyclohexyl)-acetic acid

4-Nitrophenyl acetic acid (70 g, 0.386 mol) was treated in 1 liter of0.35 M NaOH with 40 g Raney nickel catalyst at 3000 pounds per squareinch (psi) of hydrogen pressure for 173 hours. The mixture was cooled,the catalyst was filtered, and the filtrate was concentrated to a volumeof 600 mL and treated with 90 g (0.412 mol) di-tert-butyl dicarbonate inTHF (1400 mL) for 16 hours at room temperature. THF was removed byconcentration, and the pH was adjusted to 11 with 2N NaOH. Neutralmaterial was extracted with Et₂ O, and the aqueous phase was treatedwith potassium bisulfate (KHSO₄) to bring the pH to 4. A whiteprecipitate formed and was filtered off, washed with water, and dried.Recrystallization from ethyl acetate yielded the puretrans-(4-tert-butoxycarbonylaminocyclohexyl)-acetic acid, 42 g (42%); mp161-163° C.

Step 2: Preparation oftrans-{4-[2-Oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamicacid tert-butyl ester

To a colution containingtrans-(4-tertbutoxycarbonylamino-cyclohexyl)-acetic acid (15.44 g, 0.06mol), triethylamine (6.05 g, 0.06 mol) and 1-phenylpiperazine (9.73 g,0.06 mol) in CH₂ Cl₂ (250 mL) was added EDAC-HCl((1-ethyl-(3dimethylaminopropyl)-carbodiimide hydrochloride (11.5 g,0.06 mol)). The reaction mixture was stirred at room temperature 16hours, then washed with water, 1N NaOH, brine, and dried (MgSO₄). Thesolvent was evaporated, and the residue was chromatographed on a flashsilica gel column eluting with CH₂ Cl₂ and then EtOAc. The productfractions were recrystallized from acetonitrile (CH₃ CN) to yield 12.0 g(50%) oftrans-{4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-cylohexyl}-carbamicacid tert-butyl ester as white crystals; mp 197.5-200° C.

Step 3: Preparation oftrans-{4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-cylohexyl}-amine

Trans-{4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-cylohexyl}-carbamicacid tert-butyl ester (18.1 g, 0.045 mol) was taken up in MeOH (275 mL)and treated with 4 M HCl in dioxane (56 mL, 0.224 mol) and allowed tostand 22 hours. Concentration to dryness yielded a solid which wastreated with 2N NaOH (175 mL) and extracted with CH₂ Cl₂. The extractswere washed with water, brine, and dried (Na₂ SO₄). After evaporation ofthe solvent, the residue was crystallized in Et₂ O yieldingtrans-{4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine asa white solid, 11.2 g (83%); mp 90-93° C.

Step 4: Preparation oftrans-N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexylamine

A suspension of LiAlH₄ (3.32 g, 0.0875 mol) in dry THF (125 mL) at 0°was treated with a solution of AlCl₃ (40 g, 0.03 mol) in dry Et₂ O (125mL) and stirred for 30 minutes. Over a 10-minute period, a solution oftrans-{4-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine(10.54 g, 0.035 mol) in THF (150 mL) was added, and the reaction mixturewas allowed to warm to room temperature. After 20 hours, the reactionmixture was cooled in ice-water and treated with THF (50 mL) containingH₂ O (3 mL), then with 50% NaOH (3 mL) and H₂ O (6 mL). The inorganicmaterial was filtered off through a Celite pad, and the solids werewashed thoroughly with THF. The combined filtrates were evaporated todryness, and the residue was taken up in CH₂ Cl₂, dried (Na₂ SO₄), andconcentrated to yieldtrans-N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexylamine as awhite solid, 9.64 g (96%), which was used without further purification;mp 65-70° C.

Step 5: Preparation oftrans-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-trifluoromethyl-pyrimidin-2-yl)-amine

A solution of 2-chloro-4-trifluoropyrimidine (0.44 g, 2.4 mmol),trans-N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexylamine (0.576 g,2.0 mmol) and triethylamine (1.45 g, 14.0 mmol) in absolute EtOH (100mL) was heated under reflux 20 hours. The reaction mixture wasevaporated to dryness, and the residue was taken up in CH₂ Cl₂ andwashed with 1 M K₂ CO₃, brine, and dried (Na₂ SO₄). The solvent wasevaporated, and the residue was chromatographed on a flash silica gelcolumn eluting with CH₂ Cl₂ and then EtOAc. The product fractions wererecrystallized from Et₂ O-hexane to yieldtrans-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-4-trifluoromethyl-pyrimidin-2-yl)-amine0.55 g (63%) white crystals; mp 164-165° C.

EXAMPLE 35trans-(5-Methoxy-pyrimidin-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cylohexyl}-amine

Step 1: Preparation oftrans-N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cylohexyl}-N,N'-dicarbobenzyloxyguanidine

A solution oftrans-N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cylohexylamine (0.43 g,1.5 mmol), S-methyl-N,N'-dicarbobenzyloxy isothiourea (Nowak K. andKania L., Rocz. Chem., 1969;43(11):1953-1960) (0.59 g, 1.65 mmol) andtriethylamine (0.18 g, 1.8 mmol) in dimethylformamide (DMF) (50 mL) wasstirred at room temperature 3 days. An additional amount of the startingamine (0.075 g, 0.26 mmol) was added, and the reaction mixture wasallowed to stand one more day and then evaporated to dryness. Theresidue was recrystallized from Et₂ O-hexane to yieldtrans-N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl-N,N'-dicarbobenzyloxyguanidine 0.568 g (63%) white solid; mp 136-137° C.

Step 2: Preparation oftrans-N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexylguanidine

Trans-N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]cyclohexyl-N,N'-dicarbobenzyloxyguanidine(2.77 g, 4.63 mol) was hydrogenolyzed in MeOH (250 mL) under 48 psihydrogen pressure in the presence of 20% palladium on carbon catalyst(0.25 g). Filtration of the reaction mixture, evaporation of thefiltrate, and recrystallization of the residue from isopropanol(i-PrOH)-Et₂ O yielded 1.39 g (91%) of the product; mp 140-170° C.

Step 3: Preparation oftrans-(5-Methoxy-pyrimidin-2-yl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine

A solution of 2-methoxy-3-(dimethylamino)-acrolein (Plumpe H. and SchegkE., Archiv. der Pharmazie, 1967;300:704-708) (0.452 g, 3.5 mmol),trans-N-{4-[2-4-phenyl-piperazin-1-yl)-ethyl]-cyclohexylguanidine (1.15g, 3.5 mmol) and 1 M sodium methoxide (NaOMe) (7.5 mL) in MeOH (10 mL)was heated under reflux 20 hours. The mixture was cooled, the productfiltered off, washed with H₂ O, and recrystallized from CH₃ CN to yielda tan solid, 0.41 g (30%); mp 170-173° C.

In a process analogous to Example 35 using appropriate startingmaterials, the corresponding compounds of Formula I (Examples 36-38) areprepared as follows:

EXAMPLE 36trans-(5-Methyl-pyrimidin-2-yl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine

Prepared in 34% yield from commercially available2-methyl-3-(dimethylamino)-acrolein; mp 190° C.

EXAMPLE 37trans-(5-Phenyl-pyrimidin-2-yl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine

Prepared in 4% yield from phenylmalonaldehyde (Coppola G., Hardtmann G.,and Huegi B., J. Hetorocyclic Chem., 1974;11(1):51-56); mp 170° C.

EXAMPLE 38trans-(4,6-Dimethyl-pyrimidin-2-yl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine

Prepared in 12% yield from 2,4-pentanedione; mp 127-129° C.

We claim:
 1. A compound of Formula I ##STR36## wherein R is heteroaryl;R¹ is hydrogen,lower alkyl, cycloalkyl, aryl, or benzyl; n is an integerfrom 1 to 2; R² is ##STR37## wherein R³ is 2-pyrimidinyl, 2-pyrimidinylsubstituted by 1 to 2 substituents selected from the group consistingoflower alkyl, lower alkoxy, and halogen, 2-quinazolinyl,4-quinazolinyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 2-thiazolyl,2-pyrazinyl, phenyl, or phenyl substituted by 1 to 4 substituentsselected from the group consisting oflower alkyl, lower alkoxy, hydroxy,halogen, and trifluoromethyl; andthe corresponding cis and trans isomersthereof; or a pharmaceutically acceptable acid addition salt thereof. 2.A compound according to claim 1, in whichR is 2-, 3-, or4-pyridinyl,2-,3-, or 4-pyridinyl substituted by lower alkyl, 2- or4-pyrimidinyl, 2- or 4-pyrimidinyl substituted by 1 to 2 substituentsselected from lower alkyl, lower alkoxy, aryl, trifluoromethyl, orhalogen, 4-quinazolinyl, 2-pyrazinyl, 2-thiazolyl, 2-benzothiazolyl,2-benzoimidazolyl, or 2-benzoimidazolyl substituted by lower alkyl; R¹is hydrogen or methyl; n is an integer of 2; R² is ##STR38## wherein R³is 2-pyrimidinyl, 2-, 3-, or 4-pyridinyl,2- or 3-thienyl, 2-thiazolyl,2-pyrazinyl, phenyl, or phenyl substituted by 1 to 4 substituentsselected from the group consisting of lower alkyl,lower alkoxy, hydroxy,halogen, and trifluoromethyl.
 3. A compound according to claim 2, inwhichR is 2-, 3-, or 4-pyridinyl,2-(3-methyl-pyridinyl), 2-, or4-pyrimidinyl, 2-(4-methyl-pyrimidinyl), 2-(5-methyl-pyrimidinyl),2-(5-methoxy-pyrimidinyl), 2-(5-phenyl-pyrimidinyl),2-(4-trifluoromethyl-pyrimidinyl), 2-(5-fluoro-pyrimidinyl),2-(4,6-dimethyl-pyrimidinyl), 4-quinazolinyl, 2-pyrazinyl, 2-thiazolyl,2-benzothiazolyl, or 2-(1(N)-methyl-H-benzoimidazolyl; R¹ is hydrogen ormethyl; n is an integer of 2; R² is ##STR39## wherein R³ is2-pyrimidinyl, 2-, 3-, or 4-pyridinyl,2- or 3-thienyl, 2-thiazolyl,2-pyrazinyl, phenyl, or phenyl substituted by 1 to 2 substituentsselected from the group consisting oflower alkyl, lower alkoxy, hydroxy,halogen, and trifluoromethyl.
 4. A compound according to claim 3selected from the group consistingof:cis-{4-[2-(4-Pyridin-2-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-aminehydrochloride;trans-{4-[2-(4-Pyridin-2-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine;trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine;trans-(4-{2-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;trans-(4-{2-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-methyl-pyrimidin-2-yl-amine;trans-(4-{2-[4-(2,3-Dimethyl-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;trans-{4-[2-(4-Pyridin-2-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-quinazolin-4-yl-amine;trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-quinazolin-4-yl-amine;cis-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-quinazolin-4-yl-amine;cis-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-aminehydrochloride;trans-Methyl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine;trans-(5-Fluoro-pyrimidin-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;trans-Pyrimidin-2-yl-(4-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-cyclohexy)-amine;trans-(4-{2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;trans-Pyrimidin-2-yl-{4-[2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;trans-(4-{2-[4-(4-Fluoro-phenyl)-piperazin1-yl]-ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;trans-Pyrimidin-2-yl-{4-[2-(4-thiazol-2-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;trans-(4-{2-[4-(4-Methoxy-phenyl)-piperazin1-yl]-ethyl}-cyclohexyl)-pyrimidin-2-yl-amine;trans-Pyrimidin-2-yl-{4-[2-(2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-yl)-ethyl]-cyclohexyl}-amine;trans-{4-[2-(4-Pyridin-3-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine;trans-4-(4-{2-[4-(Pyrimidin-2-ylamino)cyclohexyl]-ethyl}-piperazin-1-yl)-phenol;trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyridin-3-yl-aminetrans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyridin-2-yl-amine;trans-(4-Methyl-pyrimidin-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-thiazol-2-yl-amine;trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrazin-2-yl-amine;trans-Benzothiazol-2-yl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;cis-(1-Methyl-1H-benzoimidazol-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl-}cyclohexyl}-amine;trans-(1-Methyl-1H-benzomidazol-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]cyclohexyl}-pyrimidin-4-yl-amine;trans-(3-Methyl-pyridin-2-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-amine;trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]cyclohexyl}-pyridin-4-yl-amine;trans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]cyclohexyl}-4-trifluoromethyl-pyrimidin-2-yl)amine;trans-(5-Methoxy-pyrimidin-2-1-yl)-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cylohexyl}-amine;trans-(5-Methyl-pyrimidin-2-yl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}amine;trans-(5-Phenyl-pyrimidin-2-yl-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}amine;andtrans-(4,6-Dimethyl-pyrimidin-2-yl-{4-[2-(4phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}amine.5. A compound according to claim 4 which istrans-{4-[2-(4-Phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2-yl-amine.6. A compound according to claim 1, in which R is 2-quinazolinyl, or4-quinazolinyl.
 7. A method of treating psychoses or anxiety comprisingadministering to a host suffering therefrom a therapeutic effectiveamount of a compound according to claim 1 in unit dosage form.
 8. Amethod of treating schizophrenia comprising administering to a hostsuffering therefrom a therapeutic effective amount of a compoundaccording to claim 1 in unit dosage form.
 9. A pharmaceuticalcomposition comprising a compound according to claim 1 in admixture witha pharmaceutically acceptable excipient, diluent, or carrier.
 10. Amethod of preparing a compound having the Formula I ##STR40## wherein Ris heteroaryl; R¹ is hydrogen,lower alkyl, cycloalkyl, aryl, or benzyl;n is an integer from 1 to 2; R² is ##STR41## wherein R³ is2-pyrimidinyl, 2-pyrimidinyl substituted by 1 to 2 substituents selectedfrom the group consisting oflower alkyl, lower alkoxy, and halogen,2-quinazolinyl, 4-quinazolinyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl,2-thiazolyl, 2-pyrazinyl, phenyl, or phenyl substituted by 1 to 4substituents selected from the group consisting oflower alkyl, loweralkoxy, hydroxy, halogen, and trifluoromethyl; and the corresponding cisand trans isomers thereof; or a pharmaceutically acceptable acidaddition salt thereof comprises reacting a compound of Formula II##STR42## wherein R¹, n, and R² are as defined above with a compound ofFormula III

    RX                                                         III

wherein X is Cl or Br and R is as defined above in the presence of abase and a solvent to give a compound of Formula I and optionallyseparating the mixture of cis and trans isomers of a compound of FormulaI into the individual cis or trans isomer by conventional methodologyand if desired, converting a compound of Formula I to a correspondingpharmaceutically acceptable acid addition salt by conventional meansand, if so desired, converting the corresponding pharmaceuticallyacceptable acid addition salt to a compound of Formula I by conventionalmeans.